Aerobic organisms in particular are exposed to oxidative stress throughout life. Both endogenous and exogenous factors lead to continuous production of free radicals, especially in the form of reactive oxygen species. Without an appropriate antioxidative protection, the damage, associated with the reaction of the free radicals, to cellular constituents and cellular structures would soon result in death of the cell.
Although the organism is able to avoid most of the oxidative damage, the antioxidative protection, which is very complex and consists of several hundred components in each individual cell, does not appear to be comprehensive. Instead, it must be assumed that oxidative damage accumulates with increasing age, suggesting that this is an essential, if not the decisive, factor in the aging process. The development of cancer is also discussed in this connection.
There are at least three different superoxide dismutases (SOD for short) in human tissues. These include the cytoplasmic Cu/Zn superoxide dismutases and the mitochondrial manganese superoxide dismutase (MNSOD for short). These catalyze the decomposition of superoxide free radicals (O2−), producing hydrogen peroxide (H2O2) which can in turn be decomposed by catalases and/or glutathione peroxidases to H2O and O2.
It has been possible to show that the development of colorectal tumors and hepatic metastases thereof is associated with a significant increase in MNSOD expression (Janssen et al. J. Cancer Res Clin. Oncol. 125(6), 327-35, 1999). It was also possible to show this for lung tumors (Chung-man H J, et al. Cancer Research 1; 61(23), 8578-85, 2001) and for breast cancer cells (Zhongkui Li et al., Free Radical & Medicine 30; 260-267, 2001). It was observed in clinical studies that an increased MNSOD antigen level in colorectal carcinomas, in stomach tumors and in glioblastomas is an independent prognostic factor for the reduced survival rate of the patients investigated (Janssen A M L et al. Br. J. Cancer, 78(8) 1051-1057, 1998; Janssen A M L et al. Clinical Cancer Research vol. 6., 3183-3192, 2000; Ria F. et al. British Journal of Cancer 84(4) 529-534, 2001). On the other hand, epithelial cells from carcinomas in situ of the breast and benign hyperplasias were more often found to be strongly positive for MNSOD expression than neoplastic epithelial cells from invasive carcinomas of the breast (Soini Y. et al. J Pathol Sep.195(2),156-62, 2001).
Thioredoxin reductase (TXNRD for short) is a key enzyme for regulating the intracellular redox state. This enzyme catalyzes the NADPH-dependent reduction of thioredoxin disulfide and a large number of other oxidized cellular constituents (Becker K, et al. Eur. J. Biochem. 267, 6118-6125, 2000). Constitutive expression of TXNRD has been detected in various human cell types, e.g. leukocytes. According to recent studies, TXNRD expression is thought to be involved in the development of tumors (Söderberg A. et al. Cancer Research 60, 2281-2289, 2000).
Glutathione peroxidase (GPX for short) plays an important part in protection from oxidative stress. This enzyme catalyzes the decomposition of H2O2 to H2O and O2. Overexpression of GPX1 is therefore able to protect cells from oxidative destruction and appears to be important especially when MNSOD is also overexpressed, because accumulation of H2O2 is otherwise possible (Li S., et al. Cancer Research 60, 3927-3939, 2000). A reduced GPX1 expression was observed in imexonresistant RPM/8226/I myeloma cells (Dvorakova K. et al. Molecular Cancer Therapeutics 1, 185-195, 2002).
It has been possible in recent years, through the identification and characterization of disseminated cancer cells, to achieve astonishing advances in the diagnosis, prognosis and therapy of cancers. This approach is based on the realization that the disseminated cancer cells are a tumor entity independent of the primary tumor and therefore are fundamentally different from cells of the primary tumor on the basis of a different genotype and phenotype. Thus, for example, it is possible with the aid of multiparameter analyses to answer, irrespective of the status of the primary tumor, questions with prognostic and therapeutic relevance in a number of patients with breast cancer (Giesing M. et al., The International Journal of Biological Markers vol. 15 (1), 94-99, 2000.